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Prevention of cyclophosphamide-induced hemorrhagic cystitis by resveratrol: a comparative experimental study with mesna

  • Urology - Original Paper
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Abstract

Purpose

Hemorrhagic cystitis (HC) is the most common urotoxic side effect of cyclophosphamide (CP). The aim of this study was to compare the classical efficacy of mesna (2-mercaptoethane sulfonate sodium) with three different doses of resveratrol (RES) on cyclophosphamide-induced HC in rats.

Methods

Forty-six male Sprague–Dawley rats were divided into six groups. Group 1 served as a negative control (sham). Five groups received a single dose of cyclophosphamide (150 mg/kg) intraperitoneally at the same time. Groups 2, 3, 4, 5, and 6 received only CP, CP + 20 mg/kg RES, CP + 40 mg/kg RES, CP + 80 mg/kg RES, and CP + classical protocol of three doses of mesna (30 mg/kg three times), respectively. Antioxidants, cytokines, and malondialdehyde levels were measured in all groups. In addition, histopathological alterations in tissues were examined.

Results

CP administration induced severe HC with marked edema, hemorrhage, and inflammation in group 2. RES 20 mg/kg showed meaningful protection against bladder damage compared to the control group. It was seen that RES 40 mg/kg gave weaker protection but RES 80 mg/kg was not found to be effective.

Conclusion

In conclusion, marked bladder protection was found in 20 and 40 mg/kg RES applications compared to the control group, but this protection was weaker than with mesna.

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References

  1. Levine LA, Richie JP (1989) Urological complications of cyclophosphamide. J Urol 141:1063–1069

    CAS  PubMed  Google Scholar 

  2. Kranc DM, Kim J, Straus F, Levine LA (1992) Prophylactic and therapeutic carboprost tromethamine bladder irrigation in rats with cyclophosphamide-induced hemorrhagic cystitis. J Urol 148:1326–1330

    CAS  PubMed  Google Scholar 

  3. Levine LA, Jarrard DF (1993) Treatment of cyclophosphamide-induced hemorrhagic cystitis with intravesical carboprost tromethamine. J Urol 149:719–723

    CAS  PubMed  Google Scholar 

  4. Chow YC, Yang S, Huang CJ, Tzen CY, Huang PL, Su YH et al (2006) Epinephrine promotes hemostasis in rats with cyclophosphamide-induced hemorrhagic cystitis. Urology 67:636–641

    Article  PubMed  Google Scholar 

  5. Assreuy AM, Martins GJ, Moreira ME, Brito GA, Cavada BS, Ribeiro RA et al (1999) Prevention of cyclophosphamide-induced hemorrhagic cystitis by glucose–mannose binding plant lectins. J Urol 161:1988–1993

    Article  CAS  PubMed  Google Scholar 

  6. Wong TM, Yeo W, Chan LW, Mok TS (2000) Hemorrhagic pyelitis, ureteritis, and cystitis secondary to cyclophosphamide: case report and review of the literature. Gynecol Oncol 76:223–225

    Article  CAS  PubMed  Google Scholar 

  7. West NJ (1997) Prevention and treatment of hemorrhagic cystitis. Pharmacotherapy. 17:696–706

    CAS  PubMed  Google Scholar 

  8. Traxer O, Desgrandchamps F, Sebe P, Haab F, Le Duc A, Gattegno B et al (2001) Hemorrhagic cystitis: etiology and treatment. Prog Urol 11:591–601

    CAS  PubMed  Google Scholar 

  9. Batista CK, Brito GA, Souza ML, Leitão BT, Cunha FQ, Ribeiro RA (2006) A model of hemorrhagic cystitis induced with acrolein in mice. Braz J Med Biol Res 39:1475–1481

    Article  CAS  PubMed  Google Scholar 

  10. Manikandan R, Kumar S, Dorairajan LN (2010) Hemorrhagic cystitis: a challenge to the urologist. Indian J Urol 26:159–166

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  11. Korkmaz A, Topal T, Oter S (2007) Pathophysiological aspects of cyclophosphamide and ifosfamide induced hemorrhagic cystitis; implication of reactive oxygen and nitrogen species as well as PARP activation. Cell Biol Toxicol 23:303–312

    Article  CAS  PubMed  Google Scholar 

  12. Kehrer JP, Biswal SS (2000) The molecular effects of acrolein. Toxicol Sci 57:6–15

    Article  CAS  PubMed  Google Scholar 

  13. Monach PA, Arnold LM, Merkel PA (2010) Incidence and prevention of bladder toxicity from cyclophosphamide in the treatment of rheumatic diseases: a data-driven review. Arthritis Rheum 62:9–21

    Article  CAS  PubMed  Google Scholar 

  14. Dechant KL, Brogden RN, Pilkington T, Faulds D (1991) Ifosfamide/mesna. A review of its antineoplastic activity, pharmacokinetic properties and therapeutic efficacy in cancer. Drugs 42:428–467

    Article  CAS  PubMed  Google Scholar 

  15. Hensley ML, Schuchter LM, Lindley C, Meropol NJ, Cohen GI, Broder G et al (1999) American Society of Clinical Oncology clinical practice guidelines for the use of chemotherapy and radiotherapy protectants. J Clin Oncol 17:3333–3355

    CAS  PubMed  Google Scholar 

  16. Brock N, Pohl J, Stekar J (1981) Studies on the urotoxicity of oxazaphosphorine cytostatics and its prevention—I. Experimental studies on the urotoxicity of alkylating compounds. Eur J Cancer 17:595–607

    Article  CAS  PubMed  Google Scholar 

  17. Oboh G, Akomolafe TL, Adefegha SA, Adetuyi AO (2012) Attenuation of cyclophosphamide-induced neurotoxicity in rat by yellow dye extract from root of Brimstone tree (Morinda lucida). Exp Toxicol Pathol 64:591–596

    Article  CAS  PubMed  Google Scholar 

  18. Rehman MU, Tahir M, Ali F, Qamar W, Lateef A, Khan R et al (2012) Cyclophosphamide-induced nephrotoxicity, genotoxicity, and damage in kidney genomic DNA of Swiss albino mice: the protective effect of Ellagic acid. Mol Cell Biochem 365:119–127

    Article  CAS  PubMed  Google Scholar 

  19. Fulda S, Debatin KM (2006) Resveratrol modulation of signal transduction in apoptosis and cell survival: a mini-review. Cancer Detect Prev 30:217–223

    Article  CAS  PubMed  Google Scholar 

  20. Pervaiz S, Holme AL (2009) Resveratrol: its biologic targets and functional activity. Antioxid Redox Signal 11:2851–2897

    Article  CAS  PubMed  Google Scholar 

  21. De la Lastra CA, Villegas I (2007) Resveratrol as an antioxidant and pro-oxidant agent: mechanisms and clinical implications. Biochem Soc Trans 35:1156–1160

    Article  PubMed  Google Scholar 

  22. Kitada M, Koya D (2013) Renal protective effects of resveratrol. Oxid Med Cell Longev. doi:10.1155/2013/568093

    PubMed Central  PubMed  Google Scholar 

  23. Vieira MM, Macêdo FY, Filho JN, Costa AC, Cunha AN, Silveira ER et al (2004) Ternatin, a flavonoid, prevents cyclophosphamide and ifosfamide-induced hemorrhagic cystitis in rats. Phytother Res 18:135–141

    Article  CAS  PubMed  Google Scholar 

  24. Yildirim I, Korkmaz A, Oter S, Ozcan A, Oztas E (2004) Contribution of antioxidants to preventive effect of mesna in cyclophosphamide-induced hemorrhagic cystitis in rats. Cancer Chemother Pharmacol 54:469–473

    Article  CAS  PubMed  Google Scholar 

  25. Bhatia K, Ahmad F, Rashid H, Raisuddin S (2008) Protective effect of S-allylcysteine against cyclophosphamide-induced bladder hemorrhagic cystitis in mice. Food Chem Toxicol 46:3368–3374

    Article  CAS  PubMed  Google Scholar 

  26. Botta JA Jr, Nelson LW, Weikel JH Jr (1973) Acetylcysteine in the prevention of cyclophosphamide-induced cystitis in rats. J Natl Cancer Inst 51:1051–1058

    CAS  PubMed  Google Scholar 

  27. Jain SK, McVie R, Duett J, Herbst JJ (1989) Erythrocyte membrane lipid peroxidation and glycosylated hemoglobin in diabetes. Diabetes 38:1539–1543

    Article  CAS  PubMed  Google Scholar 

  28. Aebi H (1984) Catalase in vitro. Methods Enzymol 105:121–126

    Article  CAS  PubMed  Google Scholar 

  29. Ooboshi H, Ibayashi S, Shichita T, Kumai Y, Takada J, Ago T et al (2005) Postischemic gene transfer of interleukin-10 protects against both focal and global brain ischemia. Circulation 111:913–919

    Article  CAS  PubMed  Google Scholar 

  30. Sentürk S (2005) Evaluation of the anti-endotoxic effects of polymyxin-E (colistin) in dogs with naturally occurred endotoxic shock. J Vet Pharmacol Ther 28:57–63

    Article  PubMed  Google Scholar 

  31. Zhang Y, Zhao M, Jin M, Xu C, Wang C, Liu W (2010) Immunotoxicity of pyrethroid metabolites in an in vitro model. Environ Toxicol Chem 29:2505–2510

    Article  CAS  PubMed  Google Scholar 

  32. Song J, Liu L, Li L, Liu J, Song E, Song Y (2014) Protective effects of lipoic acid and mesna on cyclophosphamide-induced haemorrhagic cystitis in mice. Cell Biochem Funct 32:125–132

    Article  CAS  PubMed  Google Scholar 

  33. Sadir S, Deveci S, Korkmaz A, Oter S (2007) Alpha-tocopherol, beta-carotene and melatonin administration protects cyclophosphamide-induced oxidative damage to bladder tissue in rats. Cell Biochem Funct 25:521–526

    Article  CAS  PubMed  Google Scholar 

  34. Sener G, Sehirli O, Yegen BC, Cetinel S, Gedik N, Sakarcan A (2004) Melatonin attenuates ifosfamide-induced Fanconi syndrome in rats. J Pineal Res 37:17–25

    Article  CAS  PubMed  Google Scholar 

  35. Topal T, Oztas Y, Korkmaz A, Sadir S, Oter S, Coskun O et al (2005) Melatonin ameliorates bladder damage induced by cyclophosphamide in rats. J Pineal Res 38:272–277

    Article  CAS  PubMed  Google Scholar 

  36. Sinanoglu O, Yener AN, Ekici S, Midi A, Aksungar FB (2012) The protective effects of spirulina in cyclophosphamide induced nephrotoxicity and urotoxicity in rats. Urology 80:1392–1396

    PubMed  Google Scholar 

  37. Al-Malki AL (2012) Synergestic effect of lycopene and Melatonin against the genesis of oxidative stress induced by cyclophosphamide in rats. Toxicol Ind Health 30:570–575

    Article  PubMed  Google Scholar 

  38. Yuan ZM, Smith PB, Brundrett RB, Colvin M, Fenselau C (1991) Glutathione conjugation with phosphoramide mustard and cyclophosphamide. A mechanistic study using tandem mass spectrometry. Drug Metab Dispos 19:625–629

    CAS  PubMed  Google Scholar 

  39. Adams JD Jr, Klaidman LK (1993) Acrolein-induced oxygen radical formation. Free Radic Biol Med 15:187–193

    Article  CAS  PubMed  Google Scholar 

  40. Al-Yahya AA, Al-Majed AA, Gado AM, Daba MH, Al-Shabanah OA, Abd-Allah AR (2009) Acacia Senegal gum exudate offers protection against cyclophosphamide-induced urinary bladder cytotoxicity. Oxid Med Cell Longev 2:207–213

    Article  PubMed Central  PubMed  Google Scholar 

  41. Sehirli O, Sakarcan A, Velioğlu-Oğünç A, Cetinel S, Gedik N, Yeğen BC et al (2007) Resveratrol improves ifosfamide-induced Fanconi syndrome in rats. Toxicol Appl Pharmacol 222:33–41

    Article  CAS  PubMed  Google Scholar 

  42. Halliwell B (1996) Antioxidants in human health and disease. Annu Rev Nutr 16:33–50

    Article  CAS  PubMed  Google Scholar 

  43. Zareia M, Shivanandappa T (2013) Amelioration of cyclophosphamide-induced hepatotoxicity by the root extract of Decalepis hamiltonii in mice. Food Chem Toxicol 57:179–184

    Article  Google Scholar 

  44. Oter S, Korkmaz A, Oztas E, Yildirim I, Topal T, Bilgic H (2004) Inducible nitric oxide synthase inhibition in cyclophosphamide induced hemorrhagic cystitis in rats. Urol Res 32:185–189

    Article  CAS  PubMed  Google Scholar 

  45. Korkmaz A, Oter S, Sadir S, Coskun O, Topal T, Ozler M, Bilgic H et al (2005) Peroxynitrite may be involved in bladder damage caused by cyclophosphamide in rats. J Urol 173:1793–1796

    Article  CAS  PubMed  Google Scholar 

  46. Hamsa TP, Kuttan G (2011) Protective role of Ipomoea obscura (L.) on cyclophosphamide-induced uro- and nephro-toxicities by modulating antioxidant status and pro-inflammatory cytokine levels. Inflammopharmacology 19:155–167

    Article  CAS  PubMed  Google Scholar 

  47. Moore KW, O’Garra A, Malefyt RW, Vieira P, Mosmann TR (1993) Interleukin-10. Annu Rev Immunol 11:165–190

    Article  CAS  PubMed  Google Scholar 

  48. Huet O, Laemmel E, Fu Y, Dupic L, Aprico A, Andrews KL, Moore SL, Harrois A, Meikle PL, Vicaut E, Chin-Dusting JP, Duranteau J (2013) Interleukin 10 antioxidant effect decreases leukocytes/endothelial interaction induced by tumor necrosis factor α. Shock 39:83–88

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

This study was supported by the Afyon Kocatepe University Scientific Research Projects Coordination Unit (Project No: 12.TIP.09).

Conflict of interest

None.

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Authors and Affiliations

  1. Department of Urology, Faculty of Medicine, Afyon Kocatepe University, Adnan Kahveci Bulvarı No:67/1 Selçuklu Mah. Selçuklu Konakları A Blok Kat 3 daire:7 Uydukent, Afyonkarahisar, Turkey

    Ibrahim Keles & Mustafa Karalar

  2. Department of Pathology, Faculty of Veterinary Medicine, Afyon Kocatepe University, Afyonkarahisar, Turkey

    Mehmet Fatih Bozkurt & Hikmet Keles

  3. Department of Bioengineering (Biochemistry Division), Faculty of Chemical and Metallurgic Engineering, Yıldız Technical University, Istanbul, Turkey

    Mustafa Cemek, Ahmet Hazini & Saadet Alpdagtas

  4. Department of Pediatric Surgery, Faculty of Medicine, Sakarya University, Sakarya, Turkey

    Turan Yildiz

  5. Department of Urology, Ankara Yüksek İhtisas Training and Research Hospital, Ankara, Turkey

    Cavit Ceylan

  6. Department of Pharmacology, Faculty of Medicine, Sakarya University, Sakarya, Turkey

    Mehmet Emin Buyukokuroglu

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  1. Ibrahim Keles
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  2. Mehmet Fatih Bozkurt
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  3. Mustafa Cemek
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  7. Hikmet Keles
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Correspondence to Ibrahim Keles.

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Keles, I., Bozkurt, M.F., Cemek, M. et al. Prevention of cyclophosphamide-induced hemorrhagic cystitis by resveratrol: a comparative experimental study with mesna. Int Urol Nephrol 46, 2301–2310 (2014). https://doi.org/10.1007/s11255-014-0833-8

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  • DOI: https://doi.org/10.1007/s11255-014-0833-8

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